Heterogeneity of Treatment Effects of Hydrocortisone by Risk of Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial
Authors: Samuel J. Gentle, Matthew A. Rysavy, Lei Li, Matthew M. Laughon, Ravi M. Patel, Erik A. Jensen, Susan Hintz, Namasivayam Ambalavanan, Waldemar A. Carlo, Kristi Watterberg, Abbot R Laptook, Martin Keszler, Betty R Vohr, Angelita M Hensman, Elisa Vieira, Lucille St. Pierre, Robert T Burke, Barbara Alksinis, Melinda Caskey, Laurie Hoffman, Katharine Johnson, Mary L Keszler, Andrea Knoll, Teresa M Leach, Emily Little, Elisabeth C McGowan, Bonnie E Stephens, Victoria E Watson, Anna Maria Hibbs, Michele C Walsh, Deanne E Wilson-Costello, Nancy S Newman, Monika Bhola, Allison H Payne, Bonnie S Siner, Gulgun Yalcinkaya, William E Truog, Howard W Kilbride, Cheri Gauldin, Eugenia K Pallotto, Anne Holmes, Kathy Johnson, Allison Scott, Brenda B Poindexter, Kurt Schibler, Stephanie Merhar, Kimberly Yolton, Cathy Grisby, Traci Beiersdorfer, Tanya E Cahill, Juanita Dudley, Teresa L Gratton, Kristin Kirker, Julia Thompson, Sandra Wuertz, Richard A Polin, Michael Cotton, Ronald N Goldberg, William F Malcolm, Ricki F Goldstein, Joanne Finkle, Patricia L Ashley, Kimberley A Fisher, Kathryn E Gustafson, Deesha Mago-Shah, Mollie Warren, Carl L Bose, Janice Bernhardt, Gennie Bose, Janice Wereszczak, Diane Warner, Cindy Clark, Stephen D Kicklighter, Alexandra Bentley, Laura Edwards, Ginger Rhodes-Ryan, Donna White, David P Carlton, Barbara J Stoll, Ellen C Hale, Yvonne Loggins, Diane Bottcher, Sheena L Carter, Salathiel Kendrick-Allywood, Maureen Mulligan LaRossa, Colleen Mackie, Gloria Smikle, Lynn C Comerford, Judith Laursen, Amy Sanders, Nathalie L Maitre, Ira Adams-Chapman, Andrew A Bremer, Stephanie Wilson Archer, Rosemary D Higgins, Jon E Tyson, Amir M Khan, Kathleen A Kennedy, Ricardo A Mosquera, Andrea F Duncan, Georgia E McDavid, Nora Alaniz, Elizabeth Allain, Julie Arldt-McAlister, Debasree Sana Boral, Katrina Burson, Allison G Dempsey, Elizabeth Eason, Patricia W Evans, Carmen Garcia, Charles Green, Donna J Hall, Margarita Jiminez, Janice John, Patrick M Jones, M. Layne Lillie, Karen Martin, Sara C Martin, Carrie M Mason, Shannon L McKee, Michelle Poe, Kimberly Rennie, Shawna L Rodgers, Saba Khan Siddiki, Daniel Sperry, Emily K Stephens, Patti L Pierce Tate, Sharon L Wright, Pablo J Sanchez, Leif D Nelin, Sudarshan R Jadcherla, Jonathan L Slaughter, Patricia W Luzader, Stephanie Burkhardt, Helen Carey, Michelle Chao, Erna Clark, Erin Fearns, Christine A Fortney, Aubrey Fowler, Jennifer Grothause, Julie Gutentag, Cole Hague, Jacqueline McCool, Mary Ann Nelin, Courtney Park, Lindsay Pietruszewski, Jessica Purnell, Julie Shadd, Kristi Small, Melanie Stein, Margaret Sullivan, Rox Ann Sullivan, Christopher J Timan, Keith O Yeates, Lina Yoseff-Salameh, Sarah A Keim, Julia Newton, Katelyn Levengood, Nancy Batterson, Courtney Rice, Mohannad Moallem, Heidi M Harmon, Abhik Das, Dennis Wallace, Carla M Banna, Marie G Gantz, Jeanette O'Donnell Auman, Margaret M Crawford, Jenna Gabrio, David Leblond, Jamie E Newman, Carolyn M Petrie Huitema, Annie vonLehmden, Kristin M Zaterka-Baxter, Lei Li, Krisa P Van Meurs, David K Stevenson, Valerie Y Chock, M. Bethany Ball, Barbara Bentley, Ritu Chitkara, Alexis S Davis, Maria Elena DeAnda, Anne M DeBattista, Beth Earhart, Lynne C Huffman, Casey E Krueger, Ryan E Lucash, Melinda S Proud, Elizabeth N Hitchner Reichert, Dharshi Sivakumar, Heather Taylor, Hali E Weiss, Myriam Peralta-Carcelen, Monica V Collins, Shirley S Cosby, Fred J Biasini, Kristy A Domnanovich, Tara E McNair, Vivien A Phillips, Sally Whitley, Sheree York Chapman, Uday Devaskar, Teresa Chanlaw, Rachel Geller, Meena Garg, Isabell B Purdy, Edward F Bell, Tarah T Colaizy, John A Widness, Jane E Brumbaugh, Karen J Johnson, Jacky R Walker, Claire A Goeke, Mendi L Schmelzel, Diane L Eastman, Michelle L Baack, Lauritz R Meyer, Laurie A Hogden, Megan M Henning, Chelsey Elenkiwich, Megan Broadbent, Sarah Van Muyden, Dan L Ellsbury, Donia B Campbell, Tracy L Tud, Janell Fuller, Sundquist Beauman, Conra Backstrom Lacy, Mary Ruffner Hanson, Carol Hartenberger, Elizabeth Kuan, Sandra Jean R. Lowe, Gregory M Sokol, Lu Ann Papile, Heidi Harmon, Abbey C Hines, Carolyn Lytle, Dianne E Herron, Susan Gunn, Lucy Smiley, Leslie Dawn Wilson, Sara B DeMauro, Barbara Schmidt, Eric C Eichenwald, Haresh Kirpalani, Sorava Abbasi, Toni Mancini, Aasma S Chaudhary, Dara M Cucinotta, Judy C Bernbaum, Andrea Freeman Duncan, Kevin Dysart, Marsha Gerdes, Hallam Hurt, Jonathan Snyder, Kristina Ziolkowski, Carl T D'Angio, Ronnie Guillet, Gary J Myers, Kyle Binion, Patricia R Chess, Caitlin Fallone, Osman Farooq, Alison Kent, Dee Maffett, Joan Merzbach, Constance Orme, Michael G Sacilowski, Premini Sabaratnam, Ann Marie Scorsone, Holly I M Wadkins, Karen Wynn, Kelley Yost, Anne Marie Reynolds, Satyan Lakshminrusimha, Praveen Chandrasekharan, Stephanie Guilford, Michelle E Hartley-McAndrews, Ashley Williams, William Zorn, Emily Li, Jennifer Donato, Kimberly G McKee, Kelly R Coleman, Stephen A Bean, Carol A Coleman, Cassandra A Horihan, Myra H Wyckoff, Luc P Brion, Roy J Heyne, Diana M Vasil, Sally S Adams, Liiun Chen, Maria M De Leon, Frances Eubanks, Alicia Guzman, Elizabeth Heyne, Lizette E Lee, Linda A Madden, E Rebecca McDougald, Lara Pavageau, Pollieanna Sepulveda, Cathy Twell Boatman, Kristine Tolentino-Plata, Azucena Vera, Jillian Waterbury, Bradley A Yoder, Robin K Ohls, Mariana Baserga, Sarah Winter, Stephen D Minton, Mark J Sheffield, Carrie A Rau, Shawna Baker, Jill Burnett, Susan Christensen, Laura Cole Bledsoe, Sean Cunningham, Brandy Davis, Jennifer O Elmont, Becky Hall, Manndi C Loertscher, Trisha Marchant, Earl Maxon, Kandace M McGrath, Hena G Mickelsen, Galina Morshedzadeh, D Melody Parry, Brixen A Reich, Susan T Schaefer, Kelly Stout, Ashley L Stuart, Kimberlee Weaver-Lewis, Kathryn D Woodbury, Seetha Shankaran, Sanjay Chawla, Girija Natarajan, Beena G Sood, Rebecca Bara, Prashant Agarwal, Monika Bajaj, Kirsten Childs, Melissa February, Laura Goldston, Mary E Johnson, Bogdan Panaitescu, Eunice Hinz Woldt, John Barks, Martha Carlson, Mary K Christensen, Diane F White, Stephanie A Wiggins
Journal: JAMA Network Open (2023)

Importance Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death. Objective To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death. Design, Setting, and Participants This secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at least 7 days, including at the time of enrollment, and who were aged 14 to 28 postnatal days. Infants were enrolled between August 22, 2011, and February 4, 2018, with follow-up between 22 and 26 months of corrected age completed on March 29, 2020. Data were analyzed from September 13, 2021, to March 25, 2023. Intervention Infants were randomized to 10 days of hydrocortisone or placebo treatment. Main Outcomes and Measures Infants’ baseline risk of grades 2 to 3 BPD or death was estimated using the NICHD Neonatal BPD Outcome Estimator. Differences in absolute and relative treatment effects by baseline risk were evaluated using interaction terms in models fitted to the efficacy outcome of grades 2 to 3 BPD or death and the safety outcome of moderate or severe NDI or death by follow-up. Results Among the 799 infants included in the analysis (421 boys [52.7%]), the mean (SD) gestational age was 24.9 (1.5) weeks, and the mean (SD) birth weight was 715 (167) g. The mean estimated baseline risk for grades 2 to 3 BPD or death was 54% (range, 18%-84%) in the study population. The interaction between treatment group and baseline risk was not statistically significant on a relative or absolute scale for grades 2 to 3 BPD or death; the size of the effect ranged from a relative risk of 1.13 (95% CI, 0.82-1.55) in quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4. Similarly, the interaction between treatment group and baseline risk was not significant on a relative or absolute scale for moderate or severe NDI or death; the size of the effect ranged from a relative risk of 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, the effect of hydrocortisone vs placebo was not appreciably modified by baseline risk for grades 2 to 3 BPD or death. Trial Registration ClinicalTrials.gov Identifier: NCT01353313